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The landscape of tolerated genetic variation in humans and primates.

Gao, Hong; Hamp, Tobias; Ede, Jeffrey; Schraiber, Joshua G.; McRae, Jeremy; Singer-Berk, Moriel; Yang, Yanshen; Dietrich, Anastasia S D; Fiziev, Petko P; Kuderna, Lukas F K; Sundaram, Laksshman; Wu, Yibing; Adhikari, Aashish; Field, Yair; Chen, Chen; Batzoglou, Serafim; Aguet, Francois; Lemire, Gabrielle; Reimers, Rebecca; Balick, Daniel; Janiak, Mareike C; Kuhlwilm, Martin; Orkin, Joseph D; Manu, Shivakumara; Valenzuela, Alejandro; Bergman, Juraj; Rousselle, Marjolaine; Silva, Felipe Ennes; Agueda, Lidia; Blanc, Julie; Gut, Marta; de Vries, Dorien; Goodhead, Ian; Harris, R Alan; Raveendran, Muthuswamy; Jensen, Axel; Chuma, Idriss S; Horvath, Julie E; Hvilsom, Christina; Juan, David; Frandsen, Peter; de Melo, Fabiano R; Bertuol, Fabrício; Byrne, Hazel; Sampaio, Iracilda; Farias, Izeni; do Amaral, João Valsecchi; Messias, Mariluce; da Silva, Maria N F; Trivedi, Mihir; Rossi, Rogerio; Hrbek, Tomas; Andriaholinirina, Nicole; Rabarivola, Clément J.; Zaramody, Alphonse; Jolly, Clifford J.;...

The landscape of tolerated genetic variation in humans and primates. Thumbnail


Hong Gao

Tobias Hamp

Jeffrey Ede

Joshua G. Schraiber

Jeremy McRae

Moriel Singer-Berk

Yanshen Yang

Anastasia S D Dietrich

Petko P Fiziev

Lukas F K Kuderna

Laksshman Sundaram

Yibing Wu

Aashish Adhikari

Yair Field

Chen Chen

Serafim Batzoglou

Francois Aguet

Gabrielle Lemire

Rebecca Reimers

Daniel Balick

Mareike C Janiak

Martin Kuhlwilm

Joseph D Orkin

Shivakumara Manu

Alejandro Valenzuela

Juraj Bergman

Marjolaine Rousselle

Felipe Ennes Silva

Lidia Agueda

Julie Blanc

Marta Gut

Dorien de Vries

R Alan Harris

Muthuswamy Raveendran

Axel Jensen

Idriss S Chuma

Julie E Horvath

Christina Hvilsom

David Juan

Peter Frandsen

Fabiano R de Melo

Fabrício Bertuol

Hazel Byrne

Iracilda Sampaio

Izeni Farias

João Valsecchi do Amaral

Mariluce Messias

Maria N F da Silva

Mihir Trivedi

Rogerio Rossi

Tomas Hrbek

Nicole Andriaholinirina

Clément J. Rabarivola

Alphonse Zaramody

Clifford J. Jolly

Jane Phillips-Conroy

Gregory Wilkerson

Christian Abee

Joe H Simmons

Eduardo Fernandez-Duque

Sree Kanthaswamy

Fekadu Shiferaw

Dongdong Wu

Long Zhou

Yong Shao

Guojie Zhang

Julius D Keyyu

Sascha Knauf

Minh D Le

Esther Lizano

Stefan Merker

Arcadi Navarro

Thomas Bataillon

Tilo Nadler

Chiea Chuen Khor

Jessica Lee

Patrick Tan

Weng Khong Lim

Andrew C Kitchener

Dietmar Zinner

Ivo Gut

Amanda Melin

Katerina Guschanski

Mikkel Heide Schierup

Robin M D Beck

Govindhaswamy Umapathy

Christian Roos

Jean P Boubli

Monkol Lek

Shamil Sunyaev

Anne O'Donnell-Luria

Heidi L Rehm

Jinbo Xu

Jeffrey Rogers

Tomas Marques-Bonet

Kyle Kai-How Farh

Joshua G Schraiber

Clément J Rabarivola

Clifford J Jolly


Personalized genome sequencing has revealed millions of genetic differences between individuals, but our understanding of their clinical relevance remains largely incomplete. To systematically decipher the effects of human genetic variants, we obtained whole-genome sequencing data for 809 individuals from 233 primate species and identified 4.3 million common protein-altering variants with orthologs in humans. We show that these variants can be inferred to have nondeleterious effects in humans based on their presence at high allele frequencies in other primate populations. We use this resource to classify 6% of all possible human protein-altering variants as likely benign and impute the pathogenicity of the remaining 94% of variants with deep learning, achieving state-of-the-art accuracy for diagnosing pathogenic variants in patients with genetic diseases.


Gao, H., Hamp, T., Ede, J., Schraiber, J. G., McRae, J., Singer-Berk, M., …Jolly, C. J. (2023). The landscape of tolerated genetic variation in humans and primates. Science, 380(6648),

Journal Article Type Article
Acceptance Date Mar 22, 2023
Online Publication Date Jun 2, 2023
Publication Date Jun 2, 2023
Deposit Date Jun 7, 2023
Publicly Available Date Jun 8, 2023
Journal Science (New York, N.Y.)
Print ISSN 0036-8075
Electronic ISSN 1095-9203
Publisher American Association for the Advancement of Science
Peer Reviewed Peer Reviewed
Volume 380
Issue 6648
Keywords Animals, Primates - genetics, Whole Genome Sequencing, Humans, Gene Frequency, Genetic Variation, Base Sequence
Additional Information “This is the author’s version of the work. It is posted here by permission of the AAAS for personal use, not for redistribution. The definitive version was published in Science on June 2nd 2023 - Volume 380, DOI:


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